Pharmacogenomics (Yang) Flashcards by Adam Dyck

Four “Rights” of PM?

-Right Patient
-Right Drug
-Right Time
-Right Dose

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How many cells in the body die off and are replaced by new ones (each day)?

100 billion

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Where are checkpoints in the cell cycle located?

-G1 (before S Phase where DNA Replication occurs)

-G2 (in prep for Mitosis)

-Anaphase (within Mitotic processes)

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The Restriction Point in the cell cycle sees the cell doing what?

Full commitment to cellular division

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How many hours before DNA Replication (ie. S Phase) do we hit the R Phase in the cell cycle?

2hrs

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T or F: Microbands consist of 3-5mil BPs, 60-120 genes, & are unevenly distributed along the chromosome.

All true!

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What percentage of chromosomes encode for genes?

10%… 90% for Non-Coding Regions!

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Subunits of an Octomeric Histone Core? What Histone protein do they attach at?

-H2A, H2B, H3, H4 (two of each)

-Attach at H1

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An average gene ranges in size from 1.5 - ___kb pairs.

2000

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Promoters typically “promote” gene expression… However, what modification at the level of the Promoter represses gene transcription?

Methylation

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Describe the relative size of the Mitochondrial Genome (ie. How many BPs, Genes).

BPs: ~17 000
Genes: 38

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“ENCODE” stands for what?

(ENC)yclopedia (O)f (D)na (E)lements

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Which of the following studies looks at underlying mechanisms of DNA mutations within the genome?

Genetic Mosaicism
Genome-Wide Assoc.
Comparative Genomics
Functional Genomics
Structural Genomics

Genetic Mosaicism

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Which of the following studies looks at genetic markers & their associations with disease phenotype?

Functional Genomics
Structural Genomics
Comparative Genomics
Genome-Wide Assoc.
Genetic Mosaicism

Genome-Wide Association

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Average frequency of SNPs?

1 - 100 (0.01%) to 1 - 1000 (0.001%)

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Each gene contains approximately how many possible coding SNPs?

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If a SNP is contained within the Regulatory region of a gene, what might happen?

Changes to expression levels of a gene.

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If a SNP is contained within the 1st or 2nd codon of an AA Triplet (inside the Coding region of a gene), what might happen?

Change to protein structure (& thus protein function).

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If a SNP is contained within the 3rd codon of an AA Triplet (inside the Coding region of a gene), what might happen?

Potential change to protein structure & function, unless changing the 3rd codon of the triplet maintains translation of the same protein!

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I have two patients and want to determine the SNP frequency between them within the Coding regions of their respective genomes. How would you calculate this?

= (3 000 000 000 / 1250) x (0.10)

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I have two patients and want to determine the SNP frequency between them within the Non-Coding regions of their respective genomes. How would you calculate this?

= (3 000 000 000 / 1250) x (0.90)

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What are the two predominant mechanisms of genome evolution?

Gene Duplication & Exon Shuffling

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Types of Indels?

-Single BP Indels
-Monomeric BP Expansion
-Multi BP Repeats
-Transposon Insertions

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At what CFTR gene position do we see a three BP deletion in Cystic Fibrosis patients?

508 (Phenylalanine Deletion)

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Huntington's patients see a 35 BP expansion of triplets... What BPs are expanded upon?

CAG

The short arm of what chromosome is an example of a structural hot spot (ie. Gene region with lots of variation & associated with genetic disorders / diseases)?

Chromosome 1

A balanced translocation between Chromosomes __ & __ creates the oncogenic BCR-ABL gene (Philadelphia Chromosome)?

9 & 22

Genetics studies _____, whereas genomics studies entirety.

heredity

What is the fundamental difference between Pharmacogenomics and Pharmacogenetics?

Pharmacogenomics: What is the proper drug & dose to accommodate for genetic differences in patients? Pharmacogenetics: What individual genes are response for variable response to drugs?

What encompasses Pharmacogenomics?

-Appropriate Dose -Avoid Toxicity -Ensure Efficacy -Reduce S/Es -Develop Novel Drugs -Explain Variable Drug Response

Deficiencies in what CYP enzyme see Tamoxifen not being an effective breast cancer treatment?

CYP2D6

Which allelic variants of CYP2D6 sees a patient having increased enzyme activity? Inactive altogether? Reduced activity?

Increased: Some 2A forms Inactive: 3 - 8, 11 Reduced: 10

What can Pharmacogenomic Biomarkers describe?

-Drug Exposure / Dosing -Clinical Outcomes -S/Es -Drug Target -MOA

A patient has mixed genotypic expression of CYP2C9 (*2 / *3) & presents with epileptic seizures. Their doctor wants to initiate on Phenytoin. What would you recommend regarding their dosage regimen?

Very low doses (or different drug altogether), as this patient (based upon presenting allelic expression) will be a poor Phenytoin metabolizer.

Aside from alleles 2 & 3, what other CYP2C9 allelic copies may result in poor (or altogether zero) Phenytoin clearance?

5, 6, 8, 11

Of the following ethnicities, which one has the highest prevalence of being an intermediate CYP2C9 metabolizer? Caucasian Asian African-American Latino

Caucasian (35%)... Asians can be up to 36% in some populations but they're a spectrum.

What are the four Ps of Personalized Medicine?

-Predictive -Preventative -Personalized -Participatory

"PCR on a Chip" assesses what analytes? DNA RNA Metabolites Proteins

DNA

Largest known human gene?

DMD (Duchenne Muscular Dystrophy)... 2.5 MB pairs with 75 Exons!

How does Eteplirsen work to treat DMD?

Restores reading frame by causing Exon 51 excision.

What was the first FDA-approved cancer drug used to treat a genetic mutation (rather than cancerous types)?

Larotrectinib

Which drug causes more emergency department visits in elderly populations than any other?

Warfarin

Which CYP2C9 allelic subtypes would warrant a patient getting a lower Warfarin dose?

2, 3

1/__ drugs approved by the FDA between 2013 & 2017 was some form of a Personalized Medicine.

1/4

Within what three therapeutic sciences did we see the greatest developments of PGx-Labeled Drugs?

1) Oncology (49.4%) 2) Neurology (9.0%) 3) ID (7.9%)

Imatinib was approved for various forms of Leukemia & works in what fashion?

Inhibits BCR-ABL Tyrosine Kinase enzyme, preventing BCR-ABL positive cells from proliferating (& simultaneously induces apoptosis).

Primary treatment for Stage I Breast Cancer?

Surgery

Is chemotherapy typically offered up for treating Stage I Breast Cancer?

Nope.

Standard treatment for Stage II Breast Cancer?

Surgery

What other treatments available for Stage II Breast Cancer?

-Radiation (Including Lymph Nodes) -Chemo (Adjuvant & Neoadjuvant) -Hormonal -Targeted

Primary treatments for Stage IV Breast Cancer?

-Hormonal -Chemo (goal now to reduce cancer growth rather than curative) -Targeted

A patient is ER+, PR+, & HER2-... What form of Breast Cancer do they have?

Luminal A

A patient is ER+, PR+, & HER2+... What form of Breast Cancer do they have?

Luminal B

A patient is ER-, PR-, HER2-... What form of Breast Cancer do they have?

Triple Negative

A patient is ER-, PR+, HER2+... What form of Breast Cancer do they have?

Luminal B... Don't require ER & PR to both be positive for this diagnosis (can be positive for one surface receptor or both).

Explain Palbociclib's MOA as it pertains to breast cancer treatment.

Prevents cells from passing the Restriction Point of the cell cycle, thus DNA Synthesis cannot occur!

Palbociclib is often combined with an Aromatase Inhibitor or Fulvestrant to treat ___+, ____- Advanced or Metastatic Breast Cancer.

HR+, HER2-

T or F: HER2 signaling cascades are mediated by ligand binding to receptors & stimulation of downstream signaling mechanisms within the cell.

False... Receptor Dimerization is what triggers downstream signaling (no ID'd ligands in HER2 breast cancer).

Trastuzumab binds what subdomain of HER2 proteins?

Subdomain IV

Pertuzumab binds what subdomain of HER2 proteins?

Subdomain II

Emtansine is often combined within a conjugate drug therapy with Trastuzumab for treating HER2+ Metastatic / Early Staged HER2+ Breast Cancers. How does it work?

Cleaved from T-DM1 & elicits cytotoxic effects within breast cancer cells.

Lapatinib is often combined with anti-metabolite drugs such as Capecitabine to treat what forms of HER2+ Breast Cancer?

Advanced / Metastatic HER2+ Breast Cancer

Lapatinib demonstrates Dual-TK Inhibitory Effects... At what receptor types does it do so?

Reversibly binds to ATP-Binding Pockets of both EGFR & HER2

What cancer form is Gefitinib indicated for?

Non-Small Cell Lung Cancer (NSCLC)

Cetuximab is a MAB against ____, & is indicated for treatment of head, neck, & colorectal cancers.

EGFR

Pharmacogenomics (Yang) Flashcards

(65 cards)